Cyclic amine derivatives as EP4 receptor antagonists

Abstract

There is described a novel group of cyclic amine derivative compounds, having an EP 4 receptor antagonistic activity and specifically pharmaceutical compounds which are useful for the treatment or alleviation of Prostaglandin E mediated diseases. The present invention therefore relates to novel compounds which are selective antagonists of the EP 4 subtype of PGE 2 receptors with analgesic and antinflammatory activity, processes for their preparation, pharmaceutical compositions containing them and their use as medicaments, inter alia for the treatment or alleviation of Prostaglandin E mediated diseases such as acute and chronic pain, osteoarthritis, inflammation-associated disorder as arthritis, rheumatoid arthritis, cancer, migraine and endometriosis.

What is claimed is:  
     
       1. A cyclic amine compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or derivative thereof, wherein:
 A is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
       
       wherein
 n=0, 1 or 2 
 m=0 or 1 
 R 1  and R 2  are independently hydrogen, linear or branched C 1-3  alkyl or are joined together to form a cyclopropyl ring; 
 R 3  is H or linear or branched C 1-3  alkyl R 4  and R 5  are independently hydrogen, fluorine, linear or branched C 1-3  alkyl or are joined together to form a cyclopropyl ring, 
 Ar is
 phenyl having: 
 
 i. in 4-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl, or 
 ii. in 3-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl, provided that 
 ii.a. when A is B, both R 4  and R 5  are fluorine, linear or branched C 1-3  alkyl or joined together they form a cyclopropyl ring, 
 ii.b. A is C and m is 0 
 ii.c. A is D and m is 1,
 a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms wherein said heteroatoms independently of each others are S, O or N; or 
 a 6-membered heteroaromatic ring containing 1 to 3 N. 
 
 
     
     
       2. A cyclic amine compound of formula (I) according to  claim 1  wherein Ar is phenyl having in 4 position one substituent selected from fluorine, cyano or trifluoromethyl. 
     
     
       3. A cyclic amine compound of formula (I) according to  claim 2  wherein R 1  is hydrogen and R 2  is methyl or both R 1  and R 2  are fused together to form a cyclopropyl ring. 
     
     
       4. A cyclic amine compound according to  claim 1  wherein A is B and is of the formula IB 
       
         
           
           
               
               
           
         
         and/or pharmaceutically acceptable derivatives or salts thereof, wherein 
         n=0, 1 or 2 
         R 1  and R 2  are independently hydrogen, linear o branched C 1-3  alkyl, or are joined together to form a cyclopropyl ring, 
         R 3  is H or linear or branched C 1-3  alkyl, 
         R 4  and R 5  are independently hydrogen, fluorine, linear or branched C 1-3  alkyl or are joined together to form a cyclopropyl ring, 
         Ar is
 phenyl having: 
 
         i. in 4-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl, or 
         ii. in 3-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl, provided that both R 4  and R 5  are fluorine, linear or branched C 1-3  alkyl or are joined together to form a cyclopropyl ring,
 a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms wherein said heteroatoms independently of each others are S, O or N; or 
 a 6-membered heteroaromatic ring containing 1 to 3 N. 
 
       
     
     
       5. A cyclic amine compound of formula (IB) according to  claim 4  wherein Ar is phenyl having in 4-position at least one substituent selected from the group consisting of: fluorine, cyano and trifluoromethyl. 
     
     
       6. A cyclic amine compound of formula (IB) according to  claim 4  wherein R 1  and R 2  are methyl or are linked together to form a cyclopropyl ring. 
     
     
       7. A cyclic amine compound of formula (IB) according to anyone of  claim 4  wherein R 3  is hydrogen. 
     
     
       8. A cyclic amine compound of formula (IB) according to  claim 4  wherein R 4  and R 5  are independently selected from hydrogen, fluorine, methyl or are fused together to form a cyclopropyl ring. 
     
     
       9. A cyclic amine compound of formula (IB) according to  claim 4  wherein n is 1 and R 4  and R 5  are independently selected from hydrogen, fluorine, methyl. 
     
     
       10. A cyclic amine compound of formula (IB) according to  claim 4  wherein n is 2 and Ar is phenyl substituted in 4 position with at least one substituent selected from the group consisting of: fluorine, cyano and trifluoromethyl. 
     
     
       11. A cyclic amine compound of formula (IB) according to  claim 4  wherein n is 2, both R 4  and R 5  are fluorine or are fused together to form a cyclopropyl ring. 
     
     
       12. A cyclic amine compound according to  claim 1  wherein A is C and is of the formula IC 
       
         
           
           
               
               
           
         
       
       and/or pharmaceutically acceptable salts or derivatives thereof wherein
 m=0 or 1 
 R 1  and R 2  are independently hydrogen, linear o branched C 1-3  alkyl, or joined together they form a cyclopropyl ring, 
 R 3  is H or linear or branched (C 1-3 ) alkyl, 
 Ar is
 phenyl having
 i) in 4-position halogen, cyano or trifluoromethyl, or 
 ii) in 3-position halogen, cyano, trifluoromethyl, provided that m is 0, 
 
 a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms wherein said heteroatoms independently of each others are S, O or N; or 
 a 6-membered heteroaromatic ring containing 1 to 3 N. 
 
 
     
     
       13. A cyclic amine compound of formula (IC) according to  claim 12  wherein Ar is phenyl having in 4-position at least one substituent selected from the group consisting of: fluorine, cyano and trifluoromethyl. 
     
     
       14. A cyclic amine compound of formula (IC) according to  claim 12  wherein R 1  and R 2  are linked together to form a cyclopropyl ring. 
     
     
       15. A cyclic amine compound of formula (IC) according to  claim 12  wherein R 3  is hydrogen or methyl. 
     
     
       16. A cyclic amine compound of formula (IC) according to  claim 12  wherein m is 0 and Ar is phenyl substituted in 4 position with at least one substituent selected from the group consisting of: fluorine, cyano and trifluoromethyl. 
     
     
       17. A cyclic amine compound according to  claim 1  wherein A is D and is of the formula (ID) 
       
         
           
           
               
               
           
         
       
       and/or pharmaceutically acceptable salts or derivatives thereof wherein
 m=0 or 1 
 R 1  and R 2  are independently hydrogen, linear o branched C 1-3  alkyl, or joined together they form a cyclopropyl ring, 
 R 3  is H or linear or branched C 1-3  alkyl, 
 Ar is
 phenyl having
 i) in 4-position halogen, cyano or trifluoromethyl, or
 ii) in 3-position halogen, cyano or trifluoromethyl provided that m is 1, 
 
 
 a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms wherein said heteroatoms independently of each others are S, O or N; or 
 a 6-membered heteroaromatic ring containing 1 to 3 N. 
 
 
     
     
       18. A cyclic amine compound of formula (ID) according to  claim 17  wherein Ar is phenyl having in 4-position fluorine, cyano or trifluoromethyl. 
     
     
       19. A cyclic amine compound of formula (ID) according to  claim 17  wherein R 1  and R 2  are linked together to form a cyclopropyl ring. 
     
     
       20. A cyclic amine compound of formula (ID) according to  claim 17  wherein R 3  is hydrogen or methyl. 
     
     
       21. A cyclic amine compound of formula (ID) according to  claim 17  wherein m is 1 and Ar is phenyl substituted in 4 position with at least one substituent selected from the group consisting of: fluorine, chlorine, cyano and trifluoromethyl. 
     
     
       22. A cyclic amine compound according to  claim 1  wherein A is E and is of the formula (IE) 
       
         
           
           
               
               
           
         
       
       and/or pharmaceutically acceptable salts or derivatives thereof wherein
 R 1  and R 2  are independently hydrogen, linear o branched C 1-3  alkyl, or joined together they form a cyclopropyl ring, 
 R 3  is H or linear or branched C 1-3  alkyl, 
 Ar is
 phenyl having in 3 or 4-position halogen, cyano or trifluoromethyl, 
 a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms wherein said heteroatoms independently of each others are S, O or N; or 
 a 6-membered heteroaromatic ring containing 1 to 3 N. 
 
 
     
     
       23. A cyclic amine compound of formula (IE) according to  claim 22  wherein Ar is phenyl having in 4-position at least one substituent selected from the group consisting of: fluorine, cyano and trifluoromethyl. 
     
     
       24. A cyclic amine compound of formula (IE) according to  claim 22  wherein R 1  is hydrogen and R 2  is methyl or both R 1  and R 2  are linked together to form a cyclopropyl ring. 
     
     
       25. A cyclic amine compound of formula (IE) according to  claim 22  wherein R 3  is hydrogen or methyl. 
     
     
       26. A compound according to  claim 1  selected from the group consisting of:
 lithium (R)-4-(1-(1-(4-(trifluoromethyl)benzyl)piperidine-2carboxamido)cyclo propyl)benzoate, 
 4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro [2.5]octane-5-carboxamido)cyclo propyl) benzoic acid carboxamido)cyclopropyl)benzoic acid, 
 4-((1S)-1-(6-(4-(trifluoromethyl)benzyI)-6-azaspiro[2.5]octane-5-carboxamido) ethyl)benzoic acid, 
 4-((1S)-1-(4,4-dimethyl-1-(4-trifluoromethyl)benzyl)piperidine-2-carboxamido) ethyl)benzoic acid, 
 4-((S)-1-((R)-4,4-difluoro-1-(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido)ethyl)benzoic acid, 
 (R)-4-(1-(4,4-difluoro-1-(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido) cyclopropyl)benzoic acid, 
 4-(1-(4,4-difluoro-1-(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclo propyl)benzoic acid, 
 4-(1-(4,4-difluoro-1-(3-(trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclo propyl)benzoic acid, 
 4-(1-(4,4-difluoro-1-(3-(trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclo -propyl)benzoic acid, 
 4-(1-(3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[4.1.0]heptane-4-carboxamido) cyclopropyl) benzoic acid, 
 4-(1-((3R)-2-(4-(trifluoromethyl) benzyl)-2-azabicyclo[4.1.0]heptane-3-carboxamido)cyclopropyl)benzoic acid, 
 4-((1 S)-1(3R)-2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[4.1.0]heptane-3-carboxamido)ethyl)benzoic acid, 
 lithium 4-((S)-1-((R)-1-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamido) ethyl) benzoate, 
 4-(1-((1R,3R,5R)-2-(3-(trifluoromethyl)benzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamido)cyclopropyl)benzoic acid, and 4-(1-((1R,3R,5R)-2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[3.1.0]hexane-3-carboxannido)cyclopropyl)benzoic acid. 
 
     
     
       27. A pharmaceutical composition comprising a compound of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and/or excipient. 
     
     
       28. A method of treatment of at least one disorder selected from the group consisting of: acute and chronic pain, inflammatory pain, osteoarthritis and rheumatoid arthritis, wherein said method comprises:
 identifying a subject patient suffering from acute and chronic pain, inflammatory pain, osteoarthritis and rheumatoid arthritis and any combinations of the foregoing; and 
 administering an effective amount of a compound of formula (I) according to  claim 1  to the subject patient.